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Spinal muscular atrophy (SMA) is one of the most common inherited causes of pediatric mortality. SMA is caused by deletions or mutations in the survival of motor neuron 1 ( SMN1 ) gene, which results in SMN protein deficiency. Humans have a centromeric copy of the survival of motor neuron gene,  SMN2 , which is nearly identical to  SMN1.  However,  SMN2  cannot compensate for the loss of  SMN1  because  SMN2  has a single-nucleotide difference in exon 7, which negatively affects splicing of the exon. As a result, most mRNA produced from  SMN2  lacks exon 7.  SMN2  mRNA lacking exon 7 encodes a truncated protein with reduced functionality. Improving  SMN2  exon 7 inclusion is a goal of many SMA therapeutic strategies. The identification of regulators of exon 7 inclusion may provide additional therapeutic targets or improve the design of existing strategies. Although a number of regulators of exon 7 inclusion have been identified, the function of most splicing proteins in exon 7 inclusion is unknown. Here, we test the role of SR proteins and hnRNP proteins in  SMN2  exon 7 inclusion. Knockdown and overexpression studies reveal that SRSF1, SRSF2, SRSF3, SRSF4, SRSF5, SRSF6, SRSF7, SRSF11, hnRNPA1/B1 and hnRNP U can inhibit exon 7 inclusion. Depletion of two of the most potent inhibitors of exon 7 inclusion, SRSF2 or SRSF3, in cell lines derived from SMA patients, increased  SMN2  exon 7 inclusion and SMN protein. Our results identify novel regulators of  SMN2  exon 7 inclusion, revealing potential targets for SMA therapeutics.

Targeting SR Proteins Improves SMN Expression in Spinal Muscular Atrophy Cells